Sepsis and other critical illnesses remain significant hazards to human health. Sepsis is particularly challenging because it is associated with great heterogeneity that has kept the identification of diagnostic and predictive bi- omarkers and effective pharmacotherapy elusive. Adverse drug reactions are among the top six leading cause of morbidity and mortality in the nation. To tackle these problems, my research program employs Translational Metabolomics which bridges the translational gap between analytical and experimental techniques and the clinical application of the science of metabolomics. Specifically, it is aimed at applying metabolomics to: 1) in- crease understanding of the metabolic processes that underlie clinically challenging problems like sepsis; and 2) improve prediction of drug response (pharmacometabolomics), including adverse drug reactions. We have an innovative swine model of sepsis that faithfully recapitulates the human situation, novel point-of-care (POC) technology and can assay biospecimens using a range of analytical platforms including liquid chromatography (LC)-mass spectroscopy (MS) and quantitative nuclear magnetic resonance (NMR). Our recent progress has led to paramount findings about the mechanisms that underlie sepsis responsiveness to L-carnitine, metabolic adaptiveness and adverse drug reactions. Our pharmacometabolomics approach introduced the idea of meta- bolic provocation to identify latent sepsis phenotypes. We have also determined that blood carnitine concentra- tions serve as a signal of metabolic stress that may predispose to adverse drug reactions. Under this MIRA (R35) application, the overarching and long-term goal of my program is to move metabolomics from knowledge discovery to implementation that will drive the transformation of the care of patients with critical illnesses. To achieve this, we will address three key gaps in knowledge: 1) The metabolic crisis timeline of critical illnesses like sepsis is, and its trajectories are, poorly understood; 2) there is limited understanding of the mechanistic underpinnings that contribute to metabolic adaptiveness and flexibility in sepsis; and 3) there is an absence of fundamental understanding of the metabolic mechanisms that underlie the variance in drug response including adverse drug reactions. With the assistance of productive, ongoing collaborations with an analytical chemist and bio-informaticist, we expect this work will bring about a paradigm shift in the understanding of the mecha- nistic underpinnings of sepsis and drug response. Long-term, we expect that the found sepsis-induced meta- bolic defects, evidenced by altered carnitine and acyl-carnitine profiles, will lead to the identification of new drug target opportunities, diagnostic and prognostic biomarker candidates and new POC technology that will drive the early, reliable detection of sepsis. In addition, we will have new insights into the mechanisms that di- rect and differentiate drug response including ADRs. Collectively, this work will provide a precision medicine directive for the effective treatment of sepsis, fuel the advancement of well-informed adaptive clinical trial de- sign, and improve human health.